Our objectives are to develop mathematical models and computer simulations to examine the interplay among microvasculature rheology, blood chemistry, oxygenation and red cell sickling, and to relate them to altered physiology of sickle-cell disesse with emphasis on vascular occlusive crisis. We are developing integrative models to interpret and analyze experimental data on gelation, the dependence of sickling on intracellular concentration of deoxygenated hemoglobin SS, oxygen-dependent and independent inhibition of sickling, red cell deformability, micro-circulatory flow and hematologic compensation in sickle-cell disease and its treatment. These models, calibrated against laboratory and clinical results, yield a basic science rationale for preliminary ranking and predicting of potential treatment modalities and designing experimental and clinical studies to isolate key patho-physiological parameters. They stand surrogate for the missing animal model of the disease. We propose to extend and complete the experimental verification of our sickling biochemistry model and to complete the integration of our models of oxygen transport and blood flow in the microcirculation. This research is supported by strong collaborative arrangements with clinical and experimental investigators.